Rare sugar D-allose enhances anti-tumor effect of 5-fluorouracil on the human hepatocellular carcinoma cell line HuH-7.
d-Allose is a novel anti-tumor monosaccharide that causes cell growth inhibition, specifically of the cancer cells, by inducing the tumor suppressor gene thioredoxin interacting protein (TXNIP). The commonly used anti-tumor drug, 5-fluorouracil (5-FU), blocks the cell cycle by inhibiting thymidylate synthase, and is also known to induce TXNIP gene expression. In this study, we examined the synergistic effect of d-allose and 5-FU and the role of TXNIP on cancer cell growth. The treatment of HuH-7 cells with d-allose or 5-FU inhibited the cell growth in a dose-dependent manner (75.2+/-2.7% with 50 mM d-allose and 66.1+/-2.7% with 0.5 mug/ml 5-FU) and d-allose enhanced the anti-tumor effect of 5-FU (55.3+/-1.1 %). TUNEL analysis did not show any evidence of apoptosis with either d-allose or 5-FU treatment. 5-FU suppressed the expression of p27(kip1), p53, and cyclin E, whereas d-allose induced p53 and reduced cyclins D, A, and E. The expression of p27(kip1) remained unchanged by d-allose at transcriptional level, but increased at the protein level suggesting an increase in protein stability by TXNIP. d-Allose and to a lesser extent 5-FU induced TXNIP expression significantly (808.4+/-122.9% and 186.8+/-32.9%, respectively) and the combination of both further enhanced TXNIP expression. As d-allose has no known side effects on normal cells, the combination of d-allose and 5-FU might be a potent candidate for cancer therapy.
Yamaguchi
Fuminori
F
Department of Cell Physiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Kamitori
Kazuyo
K
Sanada
Keiko
K
Horii
Mariko
M
Dong
Youyi
Y
Sui
Li
L
Tokuda
Masaaki
M
D000970:Antineoplastic Agents / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage*; D005947:Glucose / Q000008:administration & dosage*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology* / Q000503:physiopathology*
D000970:Antineoplastic Agents; C002055:allose; D005947:Glucose; D005472:Fluorouracil